Akt activation protects hippocampal neurons from apoptosis by inhibiting transcriptional activity of p53.

Abstract

Survival factors suppress apoptosis by activating the serine/threonine kinase Akt. To investigate the molecular mechanism underlying activated Akt's ability to protect neurons from hypoxia or nitric oxide (NO) toxicity, we focused on the apoptosis-related functions of p53 and caspases. We eliminated p53 by employing p53-deficient neurons and increased p53 by infection with recombinant adenovirus capable of transducing p53 expression, and we now show that p53 is implicated in the apoptosis induced by hypoxia or NO treatments of primary cultured hippocampal neurons. Although hypoxia and NO induced p53, treatment with insulin-like growth factor-1 significantly inhibited caspase-3-like activation, neuronal death and transcriptional activity of p53. These insulin-like growth factor-1 effects are prevented by wortmannin, a phosphatidylinositol 3-kinase inhibitor. Adenovirus-mediated expression of activated-Akt kinase suppressed p53-dependent transcriptional activation of responsive genes such as Bax, suppressed caspase-3-like protease activity and suppressed neuronal cell death with no effect on the cellular accumulation and nuclear translocation of p53. In contrast, overexpression of kinase-defective Akt failed to suppress these same activities. These results suggest a mechanism where Akt kinase activation reduces p53's transcriptional activity that ultimately rescues neurons from hypoxia- or NO-mediated cell death.

• Authors: A Yamaguchi, M Tamatani, H Matsuzaki, K Namikawa, H Kiyama, M P Vitek, N Mitsuda, M Tohyama
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 276 Issue 7 Pg. 5256-64 (Feb 16 2001) ISSN: 0021-9258 [Print] United States
• PMID: 11054421 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Proto-Oncogene Proteins
• Transcription Factors
• Tumor Suppressor Protein p53
• Nitric Oxide
• Insulin-Like Growth Factor I
• DNA
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Casp3 protein, mouse
• Caspase 3
• Caspases

Topics

• Active Transport, Cell Nucleus
• Animals
• Apoptosis
• Caspase 3
• Caspases (metabolism)
• Cell Hypoxia
• Cell Nucleus (metabolism)
• Cells, Cultured
• DNA (metabolism)
• Enzyme Activation
• Hippocampus (cytology, enzymology)
• Insulin-Like Growth Factor I (pharmacology)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred CBA
• Neurons (cytology, drug effects, enzymology)
• Nitric Oxide (pharmacology)
• Protein Serine-Threonine Kinases (metabolism)
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-akt
• Transcription Factors (metabolism)
• Transcriptional Activation
• Tumor Suppressor Protein p53 (metabolism, physiology)